non-B non-C Patients Research Articles

Influence of AFP on surgical outcomes in non-B non-C patients with curative resection for hepatocellular carcinoma

To study the clinical and prognostic features of non-B non-C alpha-fetoprotein (AFP)(-)-hepatocellular carcinoma (HCC) (NBNC-AFP(-)-HCC) and the relationship between the prognostic features of HCC and hepatitis B virus surface antigen (HBsAg) status and AFP. We enrolled 227 patients who underwent hepatic resection for HCC between January 1998 and December 2007 at Sun Yat-sen University Cancer Center, all of whom were diagnosed with HCC by pathology. All patients were stratified into one of four groups (B-AFP(+)-HCC, B-AFP(-)-HCC, NBNC-AFP(+)-HCC, and NBNC-AFP(-)-HCC) according to AFP levels and HBsAg status. The clinicopathologic and survival characteristics of NBNC-AFP(-)-HCC patients were compared with those of all other three groups. Out of the 105 NBNC-HCC patients, 43 patients (40.9%) had AFP-negative HCC. There were some differences in factors between the B-AFP(+) and NBNC-AFP(-) patients, such as age, body mass index (BMI), diabetes, and ALT (P < 0.05). On univariate analysis, tumour size, secondary tumour, and portal invasion were prognostic factors for overall survival (OS) and disease-free survival (DFS) (P < 0.05). Cox multivariate regression analysis suggested that tumour size and tumour number (P < 0.05) were independent predictors. In addition, compared with the B-AFP(+)-HCC, B-AFP(-)-HCC, and NBNC-AFP(+)-HCC groups, the NBNC-AFP(-)-HCC patients had the best DFS (P < 0.05). Compared with the B-AFP(+)-HCC and NBNC-AFP(+)-HCC groups, the NBNC-AFP(-)-HCC patients had better OS (P < 0.05), and survival rates were similar to those of B-AFP(-)-HCC patients. NBNC-AFP(-)-HCC patients had a relatively favourable prognosis. It can serve as a useful marker in predicting the risk of tumour recurrence in the early stages.

Cutoff Values of Acoustic Radiation Force Impulse Two-Location Measurements in Different Etiologies of Liver Fibrosis.

Background:Acoustic radiation force impulse (ARFI) imaging is a popular modality to measure liver fibrosis. ARFI selects optimal locations for measurement under imaging guiding. However, there are concerns on study locations and observers bias. To decrease the variations, ARFI at two locations was measured with standardized protocol. This study attempted to establish its cutoff values according to Metavir fibrosis score in different etiologies.Methods:A consecutive series of patients who received liver histology study were prospectively enrolled. All cases had hemogram, liver biochemistry, viral markers, and ARFI two-location measurements within 4 weeks of histology study. A standardized protocol was performed by single technologist. We excluded patients with alanine aminotransferase >5x upper limit normal.Results:Five hundred and ten patients that included 153 seronegative for both HBsAg and anti-HCV Non-B non-C (NBNC), 33 autoimmune liver diseases (AILD), 261 chronic hepatitis B (CHB), and 63 chronic hepatitis C (CHC) were enrolled. About 83% of NBNC patients had fat cell >5%. For diagnosis of liver cirrhosis, the area under receiver operating characteristic curve of NBNC, AILD, CHB, and CHC groups was 0.937, 0.929, 0.784, and 0.937; the cutoff values for mean ARFI were 1.788, 2.095, 1.455, and 1.710 m/s, respectively. The sensitivity and specificity are both over 0.818 for patients with nonalcoholic fatty liver diseases, CHC, and AILD, but the corresponding data are only 0.727–0.756 in CHB. The Fibrosis-4 Score is as good as ARFI on fibrosis assessment in NBNC.Conclusion:The performance of ARFI two-location measurement is excellent in NBNC, AILD, and CHC, but is only satisfactory in CHB.

Occult hepatitis B virus infection and surgical outcomes in non-B, non-C patients with curative resection for hepatocellular carcinoma.

AIMTo investigate the prevalence, clinicopathological characteristics and surgical outcomes of occult hepatitis B virus (HBV) infection (OBI) in patients with non-B, non-C (NBNC) hepatocellular carcinoma (HCC).METHODSThis study retrospectively examined the cases of 78 NBNC patients with curative resection for HCC for whom DNA could be extracted from formalin-fixed paraffin-embedded tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqMan real-time polymerase chain reaction. Possibly carcinogenetic factors such as alcohol abuse, diabetes mellitus, obesity and non-alcoholic steatohepatitis (NASH) were examined. Surgical outcomes were evaluated according to disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS).RESULTSOBI was found in 27/78 patients (34.6%) with NBNC HCC. The OBI patients were significantly younger than the non-OBI cases at the time of surgery (average age 63.0 vs 68.1, P = 0.0334) and the OBI cases overlapped with other etiologies significantly more frequently compared to the non-OBI cases (P = 0.0057). OBI had no impact on the DFS, OS or DSS. Only tumor-related factors affected these surgical outcomes.CONCLUSIONOur findings indicate that OBI had no impact on surgical outcomes. The surgical outcomes of NBNC HCC depend on early tumor detection; this reconfirms the importance of a periodic medical examination for individuals who have NBNC HCC risk factors.

Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus-positive or non-B non-C patients who underwent curative resection.

The prognostic value of lymphocyte infiltration into hepatocellular carcinoma (HCC) is still controversial, and it has not been reported in hepatitis B virus (HBV)-positive or non-B non-C (NBNC) HCC. The aim of this study is to assess the prognostic significance of lymphocyte infiltrate in tumor for HBV-positive and NBNC HCC patients. This study investigated 145 HBV-positive or NBNC patients who underwent hepatectomy for HCC between January 2001 and May 2009. Cumulative recurrence rate, overall survival (OS), and clinicopathological parameters were analyzed according to lymphocyte infiltration in tumor. In patients with low lymphocyte infiltration, the 5-year recurrence rate was higher and OS was poor (86.4 and 44.1%, respectively) than that of the patients with high lymphocyte infiltration (55.3 and 83.7%, respectively). Multivariate analyses revealed that independent risk factors for recurrence were low albumin value (hazard ratio [HR] 2.33, P = 0.009), high American Joint Committee on Cancer (AJCC) T stage (HR 2.31, P < 0.0001), high α-fetoprotein (AFP) value (HR 2.06, P = 0.005), and low lymphocyte infiltration (HR 2.50, P = 0.0001). The independent risk factors for OS were low albumin value (HR 3.69, P = 0.003), high AJCC T stage (HR 2.10, P = 0.049), high AFP value (HR 3.98, P < 0.001), and low lymphocyte infiltration (HR 3.47, P = 0.001). Lymphocyte infiltrate in tumor is significantly associated high recurrence rate and poor overall survival. Evaluation of the infiltrating lymphocyte could improve the prediction of prognosis in HCC patients after curative resection.

Impact of smoking habit on surgical outcomes in non-B non-C patients with curative resection for hepatocellular carcinoma.

AIMTo analyzed the correlation between smoking status and surgical outcomes in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC), and we investigated the patients’ clinicopathological characteristics according to smoking status.METHODSWe retrospectively analyzed the consecutive cases of 83 NBNC-HCC patients who underwent curative surgical treatment for the primary lesion at Saga University Hospital between 1984 and December 2012. We collected information about possibly carcinogenic factors such as alcohol abuse, diabetes mellitus, obesity and smoking habit from medical records. Smoking habits were subcategorized as never, ex- and current smoker at the time of surgery. The diagnosis of non-alcoholic steatohepatitis (NASH) was based on both clinical information and pathological confirmation.RESULTSAlcohol abuse, diabetes mellitus, obesity and NASH had no significant effect on the surgical outcomes. Current smoking status was strongly correlated with both overall survival (P = 0.0058) and disease-specific survival (P = 0.0105) by multivariate analyses. Subset analyses revealed that the current smokers were significantly younger at the time of surgery (P = 0.0002) and more likely to abuse alcohol (P = 0.0188) and to have multiple tumors (P = 0.023).CONCLUSIONCurrent smoking habit at the time of surgical treatment is a risk factor for poor long-term survival in NBNC-HCC patients. Current smokers tend to have multiple HCCs at a younger age than other patients.

Suppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non-B non-C hepatitis pathogenesis.

Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase. In mice, mSirt1 deficiency causes the onset of fatty liver via regulation of the hepatic nutrient metabolism pathway. In this study, we demonstrate SIRT1 expression, activity and NAD+ regulation using noncancerous liver tissue specimens from hepatocellular carcinoma patients with non-B non-C (NBNC) hepatitis. SIRT1 expression levels were higher in NBNC patients than in healthy donors, while SIRT1 histone H3K9 deacetylation activity was suppressed in NBNC patients. In the liver of hepatitis patients, decreased NAD+ amounts and its regulatory enzyme nicotinamide phosphoribosyltransferase expression levels were observed, and this led to inhibition of SIRT1 activity. SIRT1 expression was associated with HIF1 protein accumulation in both the NBNC liver and liver cancer cell lines. These results may indicate that the NBNC hepatitis liver is exposed to hypoxic conditions. In HepG2 cells, hypoxia induced inflammatory chemokines, such as CXCL10 and MCP-1. These inductions were suppressed in rich NAD+ condition, and by SIRT1 activator treatment. In conclusion, hepatic SIRT1 activity was repressed in NBNC patients, and normalization of NAD+ amounts and activation of SIRT1 could improve the inflammatory condition in the liver of NBNC hepatitis patients.

The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis

The single nucleotide polymorphism (SNP) rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with hepatic fat accumulation and disease progression in patients with non-alcoholic fatty liver disease and alcoholic liver disease (ALD). This study was conducted to determine whether PNPLA3 rs738409 SNPs affect development and prognosis of hepatocellular carcinoma (HCC) in patients with various liver diseases. We enrolled 638 consecutive Japanese patients newly diagnosed with HCC between 2001 and 2010: 72 patients with hepatitis B virus (HBV), 462 with hepatitis C virus (HCV), and 104 with non-B non-C (NBNC). NBNC patients exhibited large tumors of advanced TNM stages at HCC diagnosis, and had significantly poorer prognosis than HBV or HCV patients (P<0.001 and <0.001, respectively; log-rank test). The G/G genotype of PNPLA3 rs738409 SNP had significantly higher distribution in NBNC patients (P<0.001) and was significantly associated with higher body mass index (BMI) and an increased aspartate aminotransferase to platelet ratio index. No significant differences were observed in survival with differences in PNPLA3 SNP genotypes among the patients, although ALD patients with the G/G genotype of PNPLA3 SNP and low BMI had significantly poorer survival than those with high BMI (P=0.028). The G/G genotype of PNPLA3 rs738409 SNP was more frequently distributed, and associated with BMI and fibrosis among NBNC-HCC patients but not among HBV or HCV patients. These genotypes might affect HCC prognosis in ALD patients, but not in HBV, HCV, or NAFLD patients.

Up-regulation of dbpA mRNA in hepatocellular carcinoma associated with metabolic syndrome.

Metabolic syndrome (MS) is a group of recognized risk factors for the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. The aim of this study was to analyze the clinicopathological characteristics of HCC patients with MS and the risk factors for recurrence. Also, the aim was to investigate the cold shock protein: DNA-binding protein A (dbpA) expression in HCC patients with MS. A total of 243 patients who underwent curative resections for HCC were classified into two groups. dbpA expression was investigated in 66 HCC patients with MS and in 30 patients without MS by using real-time RT-PCR. Promoter methylation status was examined by using MS-PCR. The incidence of metabolic factors affect the HCC significantly higher in non-B non-C patients than in hepatitis B virus (HBV) or hepatitis C virus (HCV) patients (P<0.001). Univariate analysis of HCC patients with MS recurrence revealed aspartate amino transferase (AST), multiple tumors, liver damage, hepatic vein invasion, advanced cancer stages (P<0.01), alpha-fetoprotein (AFP) and diabetes mellitus type II (P<0.05) as risk factors. Multivariate analysis, AST, multiple tumors, and hepatic vein invasion (P<0.01) were identified as independent factors for the recurrence. dbpA mRNA was higher in patients with MS than in those without MS (P=0.016), and it was mostly upregulated in non-B non-C HCC patients with MS than in non-B non-C HCC patients without HBV or HCV. Especially, in HCC patients with diabetes mellitus type II, the mRNA and protein levels were highly upregulated. The dbpA expression was regulated by promoter methylation status (P<0.05). This study identifies that dbpA may accelerate the hepatocarcinogenesis in HCC patients with MS via inflammation-induced and oxidative stress pathways. The demethylation-related epigenetic activation may be one of the regulating factors for HCC patients with MS.

A weak association between occult HBV infection and non-B non-C hepatocellular carcinoma in Japan

In Japan, approximately 10% of hepatocellular carcinoma (HCC) patients are negative for both hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), i.e., they constitute the so-called category of non-B non-C (NBNC) HCC. Little is known about the characteristics of NBNC-HCC. Potential risk factors for carcinogenesis (including occult HBV infection [HBsAg is negative but HBV DNA is positive by polymerase chain reaction (PCR)], obesity, and diabetes) were assessed in 233 HCC patients grouped according to hepatitis virus serological status (152 with HCV-HCC, 36 with HBV-HCC, and 45 with NBNC-HCC). The prevalence of patients with obesity or diabetes was significantly higher in the NBNC-HCC group than in the HBV-HCC group. The same trend was observed even when patients with massive alcohol intake were excluded from the analysis. Only 8 patients (18%) in the NBNC-HCC group had detectable serum HBV DNA, and this was at very low levels (HBV/Ce/C2 and HBV/D were determined in 7 and 1 patients, respectively). In the NBNC-HCC group, the determined nucleotide sequences of the enhancer II/core promoter/precore/core region did not contain any HCC-associated mutations, whereas 25 of 30 patients in the HBV-HCC group carried strains with C1653T, T1753V, and/or A1762T/G1764A mutations. A weak association between occult HBV infection and HCC development was observed in the NBNC patients. This study indicates that nonalcoholic steato-hepatitis should be further investigated to assess its contribution to HCC development in this category of patients.

Clinicopathological features of hepatocellular carcinomas (HCCs) arising in patients without chronic viral infection or alcohol abuse: a retrospective study of patients undergoing hepatic resection

This study was carried out to clarify the etiology and clinicopathological features of hepatocellular carcinomas (HCCs) arising in patients without chronic viral infection or alcohol abuse. HCC patients who underwent resection were divided into three groups: a non-B non-C (NBNC) group (n = 13), who were seronegative for hepatitis B surface antigen (HBs Ag) and anti-hepatitis C antibody (HCV Ab), excluding a history of alcohol abuse; a B group (n = 25), who were seropositive for HBs Ag only; and a C group (n = 116), who were seropositive for HCV Ab only. We analyzed the features of tumor- and host-related factors and the outcome of the NBNC group. Hepatic inflammation and fibrosis were less severe in the NBNC group than in the other groups. There were no significant differences in tumor-related factors, except for higher serum levels of alpha-fetoprotein in the NBNC group. Recurrence rates and disease-free survivals were comparable among the three groups. The NBNC group comprised a greater population with one or two recurrent hepatic lesions (P < 0.05), and indocyanine green retention rates and fibrosis scores were preserved after the initial hepatectomy. The NBNC group had higher resection rates for intrahepatic recurrences (75.0%) than the other groups (21.1% and 22.2% in groups B and C, respectively; P < 0.05 and P < 0.05). The survival rate after the initial hepatectomy or detection of the recurrent lesions was significantly better in the NBNC group (both 100% at 5 years) than those in groups B and C (P < 0.05). NBNC patients maintained good liver function following the initial hepatectomy, and tended to have one or two recurrent lesions. These biological advantages provided NBNC patients more opportunities for repeat resection of intrahepatic recurrences, which may lead to a favorable outcome.